Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the killing effect of 4-S-cysteaminylphenol (4-S-CAP), a newly synthesised melanin precursor, on B16 melanoma cell lines possessing different melanin-producing activities and found it to be particularly effective in heavily melanised melanoma cells, but less so in moderately melanised melanoma cells, and having no effect on amelanotic melanoma cells and nonmelanoma cells. Thus, it was found that the killing effect of 4-S-CAP is highly dependent upon the synthesis of melanin and tyrosinase in melanoma cells, suggesting that 4-S-CAP may become toxic to melanoma cells only after oxidation by tyrosinase. The killing activity of 4-S-CAP also was found to be associated with a profound inhibition of the thymidine incorporation in pigmented melanoma cells, as compared to the uridine and leucine incorporation. Further, the inhibition of DNA synthesis was most pronounced in heavily melanised melanoma cells, less so in moderately melanised melanoma cells, and not seen in amelanotic melanoma cells. As a possible mechanism that might account for this action, it may be that 4-S-CAP is oxidised by tyrosinase to the o-quinone form via the catechol derivative and that some of the quinones then conjugate with sulfhydryl enzymes including DNA polymerase, thus exerting a killing activity for pigmented melanoma cells. Thus, 4-S-CAP appears to provide a new, effective cytotoxic agent for rational chemotherapy of malignant melanomas.
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PMID:The killing effect of 4-S-cysteaminylphenol, a newly synthesised melanin precursor, on B16 melanoma cell lines. 199 95

An experimental study using human melanoma (NEL-MI), rat hepatoma (Fu5-5), and human kidney (293-31) cell lines was undertaken in order to evaluate the antitumor activity of 4-hydroxyanisole (4-OHA) in vitro. Prior reports have indicated highly specific antitumor activity of 4-OHA against melanoma cells in vitro. This specific antitumor activity has been proposed to be due to the oxidation of 4-OHA by tyrosinase to cytotoxic oxidation products. Dose-dependent cytotoxicity was observed when cells were cultured for 72 h in the presence of 4-OHA. At 100 microM, 4-OHA produced growth inhibition of 62%, 32%, and 55% in melanoma, hepatoma, and kidney cell lines, respectively. No effect was seen at 10 microM 4-OHA. 1,000 microM 4-OHA produced 100% kill. Tyrosinase activity was detected only in melanoma cells. The effect of 100 microM 4-OHA on the incorporation of 3H DNA precursors in melanoma, hepatoma, and kidney cells was also studied. Thymidine incorporation was inhibited in all three cell lines at the lowest cell density tested, with the greatest inhibition seen on melanoma cells. As cell density increased, the effect of 4-OHA on thymidine incorporation decreased. With respect to RNA synthesis, 4-OHA significantly reduced the incorporation of uridine in all three cell lines, with the greatest effect in melanoma cells. Cell density also affected the inhibition of uridine incorporation, but to a lesser extent than that observed on thymidine incorporation. The effect of 4-OHA on leucine incorporation was modest and uninfluenced by cell density. Thus, cytotoxicity of 4-OHA may involve two different mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specificity of growth inhibition of melanoma by 4-hydroxyanisole. 249 44

L-glutamic acid, gamma-(p-hydroxyanilide), is a naturally occurring metabolic inhibitor found in mushrooms and shown to be active against B-16 melanoma in vivo. We have prepared and evaluated 2 analogs, the 3,4- and 2,5-dihydroxy derivatives, since these might represent more immediate precursors to the putative biologically active quinone. Both dihydroxy derivatives were more toxic than the parent phenol. The 2,5-dihydroxy derivative was significantly more cytotoxic with a 5-fold decrease in IC50 for both human and B-16 melanoma cells in vitro. In the presence of mushroom tyrosinase, both derivatives were potent inhibitors of isolated DNA polymerase with essentially complete inhibition occurring at concentrations of 10(-5) M. The 3,4-dihydroxy derivative exerted inhibitory effects primarily upon thymidine incorporation into melanoma cells in vitro while the 2,5-dihydroxy derivative also inhibited uridine and leucine incorporation. There was no significant antitumor activity observed in the B-16 system, a fact which might be attributed to the increased toxicity of the compounds.
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PMID:Antitumor effects of L-glutamic acid dihydroxyanilides against experimental melanoma. 676 71

Levodopa and dopamine are naturally occurring catecholamines with antitumor activity in several experimental tumor systems. Previous studies suggested that their cytotoxic effect was related in part to their inhibitory effect upon DNA polymerase. We have examined the effects of levodopa, dopamine, levodopa methyl ester, norepinephrine, and the analog 3,4-dihydroxybenzylamine upon human and murine melanoma cells. When exponentially growing cells were exposed to these drugs, a characteristic inhibition of thymidine incorporation was observed with much less inhibition of either uridine or leucine incorporation. In order to ascertain that inhibition was occurring at the level of DNA synthesis, we examined the effects of the drugs upon the incorporation of thymidine triphosphate by permeabilized melanoma cells. When melanoma cells were permeabilized by lysolecithin, thereby permitting the direct incorporation of labeled thymidine triphosphate, a similar inhibition of incorporation was observed. Dopamine at a concentration of 4.8 microM caused a 50% reduction in incorporation of label. These results suggested that inhibition did occur at the level of DNA synthesis. In the presence of the melanocyte-specific oxidase, tyrosinase, these derivatives are potent inhibitors of isolated DNA polymerase alpha with 50% inhibitory concentrations between 1 and 10 microM. The inhibition could be completely prevented by the presence of reducing agents such as dithiothreitol (1.0 mM). The quinols themselves were not inhibitors of DNA polymerase. Dopamine analogs represent an interesting class of antitumor agents with inhibitory activity for DNA polymerase.
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PMID:Levodopa and dopamine analogs as DNA polymerase inhibitors and antitumor agents in human melanoma. 676 47

Genome editing using programmable nucleases such as CRISPR/Cas9 or Cpf1 has emerged as powerful tools for gene knock-out or knock-in in various organisms. While most genetic diseases are caused by point mutations, these genome-editing approaches are inefficient in inducing single-nucleotide substitutions. Recently, Cas9-linked cytidine deaminases, named base editors (BEs), have been shown to convert cytidine to uridine efficiently, leading to targeted single-base pair substitutions in human cells and organisms. Here, we first report on the generation of Xenopus laevis mutants with targeted single-base pair substitutions using this RNA-guided programmable deaminase. Injection of base editor 3 (BE3) ribonucleoprotein targeting the tyrosinase (tyr) gene in early embryos can induce site-specific base conversions with the rates of up to 20.5%, resulting in oculocutaneous albinism phenotypes without off-target mutations. We further test this base-editing system by targeting the tp53 gene with the result that the expected single-base pair substitutions are observed at the target site. Collectively, these data establish that the programmable deaminases are efficient tools for creating targeted point mutations for human disease modeling in Xenopus.
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PMID:Targeted Base Editing via RNA-Guided Cytidine Deaminases in Xenopus laevis Embryos. 2917 61